Basic derivatives of porphins and metalloporphins and process for their manufacture



' amido or Patented June 18, 1935 UNITED STATES PATENT OFFICE BASIC DERIVATIVES OF PORPHINS AND METALLOPORPHINS AND PROCESS FOR THEIR MANUFACTURE No Drawing. Application December 15, 1932 Serial No. 647,490. In Switzerland December 6 Claims.

The present process relates to the manufacture of new strongly basic porphins and their metallocompounds.

By the general name Porphins there are meant the dyestuffs contained in the blood or leaves of plants. These dyestuffs possess in their molecule a heterocyclic ring of lz-carbon and 4- nitrogen atoms and can easily be characterized by their absorption-spectra.

It has now been found that new basic porphins can be prepared by treating porphins with compounds of the general formula:

wherein A represents a primary, secondary or tertiary alcoholic or enolic hydroxylic 'or an a mono-substituted amido group, (CHy)x represents a saturated or, unsaturated aliphatic continuous or branched carbon-chain, and R1 and R2 represent hydrogen, alkyl, alkoxy, alkylamino, halogenalkyl, aryl, aralkyl, or amido groups, and may represent identical or different groups or belong tov a heterocyclic ring, whereby basic side-chains become introduced into the porphin molecule.

The compounds thus obtained possess much stronger basic properties than the porphins hitherto known and yield with strong mineral acids salts which are soluble in water to neutral solutions.

For the introduction of the basic side-chains into the porphin molecule the form in which the porphin is used as starting material is immaterial. It can be employed in hydrogenated or oxidized form or as a metal compound, whereby the latter may also be used in form of an alcoholate, base or salt.

The treatment with the basic compounds can be carried out in the usual way at low or higher temperature and in presence or absence of solvents or catalysers.

The present process allows the preparation of compounds of a quite new class, that possess besides the properties of the natural porphins; a strong basic nature. Nearly all the new compounds have in form of their salts the characteristic property of being soluble in Water to a neutral solution, which aqueous solution shows the neutral spectrum of the porphins, that until now has never been observed.

The following examples illustrate the present process, the parts being by weight:

Example 1 One part of methylphaeophorbid is heated to 70 C. with about 3 parts of asymmetrical Nediethyl-ethylene-diamine, until a test, when diluted with chloroform-ether and shaken witha 1% hydrochloric acid solution shows that the dyestuff has completely passed in the acid solution. Is this point reached, the reaction mixture is treated with a chloroform-ether mixture and the dyestufi is isolated by means of a hydrochloric acid solution. By concentrating the aqueous acid solution, the new product precipitates in form of small crystals. The free base is in the dry state a dark green powder, crystallized in form of prismatic needles. It is difiicultly soluble in ether, but soluble in water in form of its salts of strong acids. Its aqueous solutions'are neutral and show the neutral spectrum. The product obtained by this example has the following structural formula:

000cm 000cm p can HsQ-CH: HOC=NCHiGHr-N A CH2 Ha Example 2 One part of methylphaeophorbid is heated with about 3 parts of diethylaminoethanol to IOU-130 C. After cooling down the reaction mixture becomes hard; it is then treated with chloroform and about 2000 parts of ether. The etheric solution is shaken with Water in order to separate the. excess of diethylaminoethanol and the dyestuff is extracted from the etheric solution by treating same with 300 parts of a 0,1% aqueous hydrochloric acid solution. The new product can then be isolated in pure form in the usual way.

The new base is a dark green dyestuff, difficultly soluble in ether and methanol. Its salts of strong acids are soluble in water to a neutral solution and show the neutral spectrum.

The product obtained by this example has the following structural formula:

Example 3 One part of methylphaeophorbid and 4 parts of ethylenediamine are heated up to- C., and the reaction product is diluted with ethyl acetate. The basic porphin can then be isolated from this solution by extraction with hydrochloric acid.

In the form of free base it is a dark blue green dyestuff, difficultly soluble in ether. Its salts of strong acids are soluble in water toa neutral solution, showing a neutral spectrum.

The product obtained by this example has the following structural formula:

Example 5 The product obtained by this example has the following structural formula:

0 NH. CHa-CHz-N C I I CH I I II HZC==CH CH3 CH1 Example 6 One part of haematoporphyrin is heated to C. with 5 parts of diethylaminoethanol, the reaction product is dissolved in ether and ex tracted therefrom with hydrochloric acid. The hydrochloride of the new base crystallizes out from its aqueous solution in form of small hygroscopic plates. By dissolving the base in methanol, the methylester of haematoporphyrin is easily obtained.

It is also possible to introduce a metal radical into the molecule by treating the aqueous solution of salts of the base with suitable metal compounds.

The product obtained by this example has the following structural formula:

c o'o-oHPcHPN OOOH HgG-CHZ CzHi HgC-CHz Example 7 One part of phylloporphyrin is heated to C. with 5 parts of diethylaminoethanol, whereby the new basic product is formed. It crystallizes out from the reaction mixture in form of big prismatic needles and can be recrystallized from a The product obtained by this example has the The product obtained by this example has'the following structural formula: following structural formula:

' OH 0235 I v NHCH2OH:N "5 COOCH2OH2N V 5 GO C2115 CH 0211 I H2O(|3H2 1 1'1 Hloom g H HaC CH3 HaC Q'C]1a N N\ N N 10 HO on no OH ESQ-(\NH HN (|JHr H30 Y NH NH -om H3o-c :rn o11 CH3 Hao-orc g 0 3 H3 15 Example 8 Example 11 One part of the copper salt of methylphaeo- If phylloporphyrin used in Example '1 is rephorbid is heated t0 100 C. With 3 parts Of diplaced by pyrroporphyrin a new basic compound ethylaminoethylenediamine and the rwction of F, P, 133 3,, i o t w i h crystallizes product obtained is diluted with chloroform and out in form of prismatic needles and is soluble in ether- The new Strong basic p p s e water to a neutral solutionin form of its saltsv tracted from this Solution y means y The product obtained by this example has the Chloris a r n a y other u a yfollowing structural formula: The new base is a dark blue-green dyestulf soluble in organic solvents with a blue-green /C1H5 coloration. Its salts of strong acids are soluble COO--CH-OH2 -N in water to a blue-green solution.

a By using in this example the asymmetrical HzCOH H H 5 diethylaminoethylenediamine, a similar product I is obtained. H3O /7 -om The product obtained by this example has the N N" following structural formula: HO OH I (32H,

COOCH 00 NH on CH N 35 H3G-\/\NH HN on, I 3 I 1 P l H2CCH2 HCC=O C2115 o cm I H3C-CH2 H CH3 I C HaC 0113 Example 9 R 40 HO \r on One part of phylloporphyrin-methylester is heated in a closed vessel to 180 C. with 5 parts Eno- N XM of diethylaminoethylenediamine and the reac- \C tion product is treated with chloroform, filtered H3C CH= H CH3 3 and after addition of methanol concentrated, un- E l 12 til chloroform is separated. The new product ramp e crystallizes out from the methanol solution in One part of the iron salt of phylloporphyrin form of prismatic needles of F. P. 235 C. ester is heated to 160-l70 C. with 5 parts of It is a dark; red-brown dyestuff, possessing diethylaminoethanol and the reaction product is basic properties. Its salts of strong mineral treated as above described. The new base crysacids are soluble in water to a neutral solution tallizes out in form of prismatic needles from a showing the neutral spectrum. mixture of chloroform and ether and is a dark- The product obtained by this example has the brown dyestuff possessing basic properties. following structural formula: The product obtained by this example has the following structural formula:

I 6 o ONHOH2GH:N O O HZO OHZ (IJHS H HzC-GH: CH3 02m 7 H3O H3O /7\/\ CH3 N N =N E 7 HO OH HO CH s a /Fe\ 01 65 g HN E HZG CH: HsCCH z g CH3 CH3 H C 'JH2 g CH3 (3H3 Example 10 Ezwmple 13 By replacing in the preceding example phyllo- 5 parts of phaeophytin are heated under stirporphyrin-methylester by p-yrroporphyrin-rneth ring to PLO-150 C. with 25 parts of triethanolaylester, a similar dark red-brown compound of mine for 2-3 hours; then one part of copper- F. P. 211 C. is obtained. J a acetate is added to the reaction mixture and the heating is continued for a short time. Tothe product thus obtained there are then added while well Stirring;'200 parts of water, whereby the phaeophytin-coppersalt thatdid not enter into reaction becomes precipitated. The obtained mass is filtered, the filtrate concentrated to about half its volume andthe new product is precipitated therefrom by means of common salt and a small quantity of diluted hydrochloric acid.

The product thus obtained issoluble in water to neutral greensolutions.

The product obtained by this example has the following structural formula:

A mixture consisting of one part of chlorine eand 5 parts of diethylaminoethanol is heated to 'C., suspended in ether and the etheric solution is treated with a sodium carbonate solution in order to extract the unreacted part. The new product is then extracted from the etheric solution by means of diluted hydrochloric acid or in any other usual way.

Instead of chlorine e, rhodine g'may be used. With respect to the meaning of chlorine e and rhodine g, attention is directed to Untersuchungen iiber Chlorophyll: R. W illstatter und A. Stoll, Berlin 1913,.edition Springer, page 290, where it is said that phytochlorine e and phytorhodine g are themost important products of the hydrolyse of phaeophytin and other phaeophorbids. As these split products do not simply result by saponification of the two ester groups, but simultaneously by one-of several possible transformations of the lactam groups, the reaction like the saponification of the chlorophyll is highly dependent of the conditions. According to the main object, to which the hydrolyse serves, the obtainment of the phytol or the isolation of the basic split products, different, processes for the saponification of the phaeophytin come into consideration, which can be performed with alcoholic potassium lye cold and hot, but .by no means with diluents, that is not by use of etheric phaeophytin solutions. In this case, instead of the stable phytochlorine e, the weaker basic unstable chlorine g, and instead of the phytorhodine g, the weakly basic phy torhodine It would result.

The product obtained by this example has the following structural formula:

GOOH COOH Example 15 One part of haemin (chlorhaemin of protoporhyrin) is heated with 5 parts of diethylaminoethanol to 155 C.,'the solution obtained is filtered, the filtrate is treated with chloroform and the new base is isolated from thechloroform solution in any usual way.

Instead of the above cited product the iron salt of tetramethylhaematoporphyrin can be used and transformed into the basic ester.

The product obtained by this example has the following structural formula:

CHz-CH2 CzHs CQOH Example 16 One part of rhodoporphyrin-dimethy1ester is heated with 6 parts of asymmetrical N-diethylaminoethylenediamine to about C. and the new basic product is isolated from the reaction mixture in the manner described above. The new diamine crystallizes out in form of prisms.

By using protoporphyrindimethylester, a diamine which is easily soluble. in organic solvents may be prepared.

The product obtained by this example has the following structural formula:

The examples given above illustrate the process for the preparation of the new basic porphins, whereby it must be pointed out that other amines than those cited above such as ethylenediamine, triethanolamine etc., maybe used for the intro duction of the basic side chains. The extraction of the basic bodies from the reaction product may be carried out in different ways, that is by extraction with organic solvents or with suitable acids, such as sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid etc.

What we claim is: H

1. A process for the manufacture of strong oasic porphins, characterized in that porphins are heated with compounds of the general formula in which A represents ethylol or beta-aminoethyl and R represents hydrogen, ethyl or ethylol.

2. A process for the manufacture of strong basic porphins, characterized in that porphins are heated with compounds of the general formula A-N: (R) 2 in which A represents ethylol or beta-aminoethyl and R represents hydrogen, ethyl or ethylol, at a temperature of YO-180 C. V

3. A process for the manufacture of strong basic porphins, characterized in that phaeophorbidae are heated with compounds of the general formula in which A represents ethylol or beta-aminoethyl and R represents hydrogen, ethyl or ethylol, at a temperature of TO-180 C.

4. A process for the manufacture of a strong basic porphin, characterized in that phaeophorbid is heated with diethylethylenediamine at a temperature of 100 C.

5. The strong basic porphins of the general formula X[3-CH2CH2N(R) 2 wherein X represents a porphin molecule and 6 means that the amine is linked to a p-carbon of the porphin molecule, and wherein R represents hydrogen, ethyl or ethylol, which compounds are in form of their free bases soluble in organic solvents with a red-brown, blue to green-blue coloration and. that yield with strong acids water-soluble salts, yielding brown to green-blue neutral solutions, which aqueous solutions show the neutral spectrum of the porphins.

6. The diethylethylenediamine derivative of phaeophorbid, which is in dry state a darkgreen compound, soluble in organic solvents with a green coloration and which yields with strong acids water-soluble salts, which aqueous solutions are neutral and show the neutral spectrum 20 

